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COMPARATIVE STUDY
JOURNAL ARTICLE
RANDOMIZED CONTROLLED TRIAL
RESEARCH SUPPORT, N.I.H., EXTRAMURAL
RESEARCH SUPPORT, NON-U.S. GOV'T
Edoxaban Versus Warfarin in Patients With Atrial Fibrillation and History of Liver Disease.
Journal of the American College of Cardiology 2019 July 17
BACKGROUND: Patients with liver disease have increased risk of thrombosis and bleeding but are typically excluded from trials of direct oral anticoagulant agents.
OBJECTIVES: This study evaluated the pharmacokinetics (PK), pharmacodynamics (PD), clinical efficacy and safety of edoxaban versus warfarin in patients with atrial fibrillation (AF) and history of liver disease.
METHODS: ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis In Myocardial Infarction Study 48) was a randomized, double-blind trial comparing edoxaban with warfarin in patients with AF followed for 2.8 years. History of liver disease was defined as investigator-reported liver disease or >2-fold transaminase elevation at randomization. The primary efficacy and safety endpoints of stroke or systemic embolic event (SSEE) and major bleeding were assessed stratified by history of liver disease. PK/PD assessments of edoxaban included endogenous and extrinsic factor Xa activity and edoxaban concentration.
RESULTS: Among 21,105 patients, 1,083 (5.1%) had a history of liver disease; they had a higher prevalence of many comorbidities. The adjusted risks of SSEE were similar (adjusted hazard ratio [HRadj ]: 0.90; 95% confidence interval [CI]: 0.67 to 1.22; p = 0.50), but major bleeding was more common in patients with liver disease (HRadj : 1.38; 95% CI: 1.10 to 1.74; p = 0.005). There were no significant differences in PK/PD assessment of edoxaban in patients with versus without liver disease. The HRs for higher-dose edoxaban versus warfarin for SSEE were 0.86 (95% CI: 0.73 to 1.01) in patients without and 1.11 (95% CI: 0.54 to 2.30) with liver disease (p for interaction [pint ] = 0.47), major bleeding 0.80 (95% CI: 0.70 to 0.91) in patients without and 0.91 (95% CI: 0.56 to 1.47) with liver disease (pint = 0.63). There were no significant differences in hepatic adverse events between the 2 treatment groups.
CONCLUSIONS: Among patients with AF receiving oral anticoagulation, bleeding, but not thromboembolic events, was increased in patients with liver disease. A history of liver disease did not alter the relative efficacy and safety of edoxaban compared with warfarin. Hepatic adverse events were similar between edoxaban and warfarin.
OBJECTIVES: This study evaluated the pharmacokinetics (PK), pharmacodynamics (PD), clinical efficacy and safety of edoxaban versus warfarin in patients with atrial fibrillation (AF) and history of liver disease.
METHODS: ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis In Myocardial Infarction Study 48) was a randomized, double-blind trial comparing edoxaban with warfarin in patients with AF followed for 2.8 years. History of liver disease was defined as investigator-reported liver disease or >2-fold transaminase elevation at randomization. The primary efficacy and safety endpoints of stroke or systemic embolic event (SSEE) and major bleeding were assessed stratified by history of liver disease. PK/PD assessments of edoxaban included endogenous and extrinsic factor Xa activity and edoxaban concentration.
RESULTS: Among 21,105 patients, 1,083 (5.1%) had a history of liver disease; they had a higher prevalence of many comorbidities. The adjusted risks of SSEE were similar (adjusted hazard ratio [HRadj ]: 0.90; 95% confidence interval [CI]: 0.67 to 1.22; p = 0.50), but major bleeding was more common in patients with liver disease (HRadj : 1.38; 95% CI: 1.10 to 1.74; p = 0.005). There were no significant differences in PK/PD assessment of edoxaban in patients with versus without liver disease. The HRs for higher-dose edoxaban versus warfarin for SSEE were 0.86 (95% CI: 0.73 to 1.01) in patients without and 1.11 (95% CI: 0.54 to 2.30) with liver disease (p for interaction [pint ] = 0.47), major bleeding 0.80 (95% CI: 0.70 to 0.91) in patients without and 0.91 (95% CI: 0.56 to 1.47) with liver disease (pint = 0.63). There were no significant differences in hepatic adverse events between the 2 treatment groups.
CONCLUSIONS: Among patients with AF receiving oral anticoagulation, bleeding, but not thromboembolic events, was increased in patients with liver disease. A history of liver disease did not alter the relative efficacy and safety of edoxaban compared with warfarin. Hepatic adverse events were similar between edoxaban and warfarin.
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